Department of Gastroenterology, Guangzhou Women and Children's Medical Center, Guangzhou, China
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
J Virol. 2021 Jan 28;95(4). doi: 10.1128/JVI.01926-20.
Tick-borne encephalitis virus (TBEV), a major tick-borne viral pathogen of humans, is known to cause neurological diseases such as meningitis, encephalitis, and meningoencephalitis. However, the life cycle and pathogenesis of TBEV are not well understood. Here, we show that the knockdown or knockout of ADAM15 (a disintegrin and metalloproteinase 15), a host protein involved in neuroblastoma diseases, leads to TBEV replication and assembly defects. We characterized the disintegrin domain in ADAM15 and found that the ADAM15 subcellular localization was changed following TBEV infection. RNA interference (RNAi) screen analysis confirmed ADAM's nonredundant functions and identified a specific role for ADAM15 in TBEV infection. An RNA-sequencing analysis was also conducted to understand the causal link between TBEV infection and the cellular endomembrane network, namely, the generation of replication organelles promoting viral genome replication and virus production. Our data demonstrated that TBEV infection changes ADAM15 cellular localization, which contributes to membrane reorganization and viral replication. Tick populations are increasing, and their geographic ranges are expanding. Increases in tick-borne disease prevalence and transmission are important public health issues. Tick-borne encephalitis virus (TBEV) often results in meningitis, encephalitis, and meningoencephalitis. TBEV causes clinical disease in more than 20,000 humans in Europe and Asia per year. An increased incidence of TBE has been noted in Europe and Asia, as a consequence of climate and socioeconomic changes. The need to investigate the mechanism(s) of interaction between the virus and the host factors is apparent, as it will help us to understand the roles of host factors in the life cycle of TBEV. The significance of our research is in identifying the ADAM15 for TBEV replication, which will greatly enhance our understanding of TBEV life cycle and highlight a target for pharmaceutical consideration.
蜱传脑炎病毒（TBEV）是一种主要的蜱传病毒性人类病原体，已知会导致脑膜炎、脑炎和脑膜脑炎等神经系统疾病。然而，TBEV 的生命周期和发病机制尚不清楚。在这里，我们表明，参与神经母细胞瘤疾病的宿主蛋白 ADAM15（解整合素和金属蛋白酶 15）的敲低或敲除会导致 TBEV 复制和组装缺陷。我们对 ADAM15 的解整合素结构域进行了表征，并发现 TBEV 感染后 ADAM15 的亚细胞定位发生了改变。RNA 干扰（RNAi）筛选分析证实了 ADAM 的非冗余功能，并确定了 ADAM15 在 TBEV 感染中的特定作用。还进行了 RNA 测序分析，以了解 TBEV 感染与细胞内膜网络之间的因果关系，即促进病毒基因组复制和病毒产生的复制细胞器的产生。我们的数据表明，TBEV 感染改变了 ADAM15 的细胞定位，这有助于膜重排和病毒复制。蜱种群正在增加，其地理范围也在扩大。蜱传疾病的发病率和传播率增加是一个重要的公共卫生问题。蜱传脑炎病毒（TBEV）每年在欧洲和亚洲导致超过 20,000 人患脑膜炎、脑炎和脑膜脑炎。由于气候和社会经济变化，欧洲和亚洲的 TBE 发病率有所增加。显然，需要研究病毒与宿主因素之间的相互作用机制，因为这将有助于我们了解宿主因素在 TBEV 生命周期中的作用。我们的研究意义在于确定 ADAM15 是 TBEV 复制的关键，这将极大地提高我们对 TBEV 生命周期的理解，并突出一个值得药物考虑的靶点。
